A MUTATED RETINOIC ACID RECEPTOR-ALPHA EXHIBITING DOMINANT-NEGATIVE ACTIVITY ALTERS THE LINEAGE DEVELOPMENT OF A MULTIPOTENT HEMATOPOIETIC-CELL LINE

The retinoic acid receptor (RARalpha) is expressed in virtually all hematopoietic lineages, but the role of this transcription factor in regulating the growth and differentiation of hematopoietic progenitors is unknown. We have constructed a mutant RARalpha that both exhibits dominant-negative activity against the normal RARalpha in transient expression assays in mouse fibroblasts and inhibits retinoic acid-induced neutrophilic differentiation of the HL-60 human promyelocytic leukemia cell line. When this dominant-negative RARalpha construct is introduced into the multipotent interleukin-3-dependent FDCP mix A4 murine hematopoietic cell line, there is a rapid switch from spontaneous neutrophil/monocyte differentiation to basophil/mast cell development. Thus, in this multipotent hemopoietic cell line the normal RARalpha transcription factor and/or related molecules appear to promote the differentiation of neutrophils and monocytes but suppress the development of basophils/mast cells.